Paclitaxel-Carboplatin-Bevacizumab +/- Nitroglycerin in Metastatic Non-Squamous-Non-Small Cell Lung Cancer (NVALT12)

September 24, 2020 updated by: Dutch Society of Physicians for Pulmonology and Tuberculosis

A Randomized Phase II Study of Paclitaxel-carboplatin-bevacizumab With or Without Nitroglycerin Patches in Patients With Stage IV Non-squamous-non-small Cell Lung Cancer: NVALT12

This study is designed to assess the effects of adding nitroglycerin (NTG) patches, delivery 25 mg NTG per 24 h, to the standard first line treatment of metastatic non-squamous non-small cell lung cancer (NSCLC), i.e. 4 cycles of carboplatin-paclitaxel-bevacizumab, followed by bevacizumab alone until disease progression. Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. NTG is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor.

A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.

The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab containing chemotherapy improves progression free survival, response rate and overall survival in patients with metastatic non-squamous NSCLC.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Standard treatment for non-small cell lung cancer (NSCLC) consists of platinum-containing chemotherapy. It has been shown that the addition of bevacizumab to standard chemotherapy improves progression-free survival (PFS) and overall survival (OS) in patients with non-squamous NSCLC. There is a need for improved PFS and OS and response rates to chemotherapy are only 25-35%.

Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Hypoxia Inducible Factor (HIF) -1α is the major factor regulating the response to hypoxia.

HIF directly activates vascular endothelial growth factor (VEGF) and VEGF-receptor. Bevacizumab interacts with this pathway by blocking VEGF.

Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. Nitroglycerin (NTG) is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor and inhibits HIF-1α.

Interestingly, it has recently been shown in mouse models that the addition of HIF-1α inhibitors to bevacizumab significantly inhibits tumor growth by inducing apoptosis.

A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.

The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab containing chemotherapy improves PFS, response rate and OS in patients with metastatic non-squamous NSCLC.

Study Type

Interventional

Enrollment (Actual)

223

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • VU Medisch Centrum
      • Breda, Netherlands
        • Amphia Ziekenhuis
      • Den Bosch, Netherlands
        • Jeroen Bosch Ziekenhuis
      • Eindhoven, Netherlands
        • Catharina-ziekenhuis
      • Groningen, Netherlands
        • Martini Ziekenhuis
      • Maastricht, Netherlands, 6202 AZ
        • Maastricht UMC
      • The Hague, Netherlands
        • HagaZiekenhuis
      • Zwolle, Netherlands
        • Isala Klinieken

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically/cytologically proven stage IV non-squamous NSCLC (according to IASLC staging 7.0)
  • No prior chemotherapy or therapy with systemic anti-tumor therapy (e.g., monoclonal antibody therapy) or prior exposure to agents directed at the HER axis (e.g. epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), Herceptin). Prior surgery and/or localized palliative irradiation is permitted provided that the irradiated lesion is not the only measurable lesion. Prior adjuvant chemotherapy > 1 year ago and prior treatment with an EGFR-TKI for patients with an activating EGFR mutation is allowed.
  • Age ≥ 18 years.
  • ECOG Performance Status of 0 - 2.
  • Life expectancy of at least 12 weeks.
  • Subjects with at least one uni-dimensional(for RECIST) measurable lesion.
  • Adequate bone marrow, liver and renal function.
  • Adequate non-hormonal contraception for females of childbearing potential during the study and in the 6 months thereafter.
  • Adequate contraception for male participants (or their partners) during the study and in the 6 months thereafter.

Exclusion Criteria:

  • Clinically significant (i.e. active) cardiovascular disease: congestive heart failure >NYHA class 2; CVA or myocardial infarction < 6 months prior to study entry; uncontrolled hypertension (blood pressure systolic > 150 mmHg and/or diastolic > 100 mmHg).
  • Symptomatic hypotension.
  • History of hemoptysis at least grade 2 (bright red blood of at least 2,5 ml in the last 3 months)
  • Evidence of tumor invading major blood vessels on imaging (i.e. superior vena cava or pulmonary artery).
  • History of HIV infection or chronic hepatitis B or C.
  • Active clinically serious infection
  • Symptomatic metastatic brain or meningeal tumors. Patients with brain metastasis may be included the patient is treated with brain radiotherapy and asymptomatic.
  • History of organ allograft.
  • Patients with evidence or history of bleeding diathesis.
  • Non-healing wound or ulcer.
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment
  • Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry
  • Radiotherapy within 4 weeks of start of study drug. Palliative radiotherapy for bone lesions is allowed > 14 days of start of chemotherapy. Major surgery within 4 weeks of start of study.
  • Use of vasodilators (including 5-phosphodiesterase inhibitors, calcium antagonists or nitrates)
  • Autologous bone marrow transplant or stem cell rescue within 4 months of study
  • Investigational drug therapy outside of this trial during or within 4 weeks of study entry
  • Pregnancy or lactation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: carboplatin-paclitaxel-bevacizumab
paclitaxel 200 mg/m2 d1 - carboplatin area under the curve (AUC) 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression
Drug: carboplatin paclitaxel bevacizumab
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression
Other Names:
  • Avastin
  • Taxol
Experimental: standard treatment plus nitroglycerin
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression. Plus nitroglycerin transdermal patches 25 mg per day from day -3 till +2 of First combination cycle till the last bevacizumab monotherapy cycle
Drug: Standard treatment plus nitroglycerin
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression. Plus nitroglycerin transdermal patches 25 mg per day from day -3 till +2 of First combination cycle till the last bevacizumab monotherapy cycle
Other Names:
  • Avastin
  • Taxol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
progression free survival
Time Frame: every 6 weeks during chemotherapy
Imaging
every 6 weeks during chemotherapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
objective response rate
Time Frame: every 6 weeks during chemotherapy
Imaging
every 6 weeks during chemotherapy
disease control rate
Time Frame: every 6 weeks during chemotherapy
Imaging
every 6 weeks during chemotherapy
duration of response
Time Frame: every 6 weeks during chemotherapy
Imaging
every 6 weeks during chemotherapy
safety of the treatment
Time Frame: every 3 weeks during chemotherapy
adverse events, hematology, chemistry, physial examination
every 3 weeks during chemotherapy
prediction of early response
Time Frame: after 3 weeks
FDG PET scan (exploratory objective)
after 3 weeks
decreased hypoxia
Time Frame: after 6 weeks
FAZA scan (exploratory objective)
after 6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dutch Society of Physicians for Pulmonology and Tuberculosis

Investigators

  • Principal Investigator: Anne-Marie C. Dingemans, MD PhD, Maastricht UMC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2011

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

August 1, 2020

Study Registration Dates

First Submitted

July 23, 2010

First Submitted That Met QC Criteria

July 27, 2010

First Posted (Estimate)

July 28, 2010

Study Record Updates

Last Update Posted (Actual)

September 28, 2020

Last Update Submitted That Met QC Criteria

September 24, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NVALT12

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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